{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:41:31Z","timestamp":1790959291987,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Breast cancer has distinct etiology, prognoses, and clinical outcomes at premenopausal ages. Determination of the frequency of germline and somatic mutations will refine our understanding of the genetic contribution to premenopausal breast cancer susceptibility. We applied a comprehensive next generation sequencing-based approach to analyze blood and\/or tissue samples of 54 premenopausal breast cancer patients treated in our clinic. Genetic testing results were descriptively analyzed in correlation with clinicopathological data. In the present study, 42.5% of premenopausal breast cancer patients tested carried pathogenic mutations in cancer predisposition genes (CHEK2, BRCA1, TP53, and MUTYH). Germline variants of unknown\/uncertain significance (VUSs) in eight different cancer susceptibility genes, namely BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, ATM, BRIP1, and PMS2, were also identified in 14 premenopausal patients (35%). Of the breast tumors tested, 61.8% harbored pathogenic somatic variants in tumor suppressor genes (TP53, NF1, RB), genes involved in DNA repair (BRCA1, BRCA2, ATM, RAD50), cell proliferation (PTEN, PIK3C FGFR3, AKT1, ROS1, ERBB2, NOTCH1), and cell adhesion (CTNNB1). This descriptive study employs the powerful NGS technology to highlight the high frequency of premenopausal cases attributable to genetic predisposition. Mutation identification in a larger cohort may further ensure that these patients receive tailored treatment according to their menopausal status.<\/jats:p>","DOI":"10.3390\/genes13081362","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T23:37:29Z","timestamp":1659310649000},"page":"1362","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9540-7553","authenticated-orcid":false,"given":"Eleni","family":"Zografos","sequence":"first","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Andrikopoulou","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alkistis Maria","family":"Papatheodoridi","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kaparelou","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garyfalia","family":"Bletsa","sequence":"additional","affiliation":[{"name":"Hellenic Anticancer Institute, 10680 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7192-4575","authenticated-orcid":false,"given":"Michalis","family":"Liontos","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8990-3254","authenticated-orcid":false,"given":"Meletios-Athanasios","family":"Dimopoulos","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Zagouri","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA","volume":"71","author":"Sung","year":"2021","journal-title":"Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.breast.2012.08.005","article-title":"Association between common risk factors and molecular subtypes in breast cancer patients","volume":"22","author":"Turkoz","year":"2013","journal-title":"Breast"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s10549-009-0388-z","article-title":"Relationship between age at diagnosis and outcome of premenopausal breast cancer: Age less than 35 years is a reasonable cut-off for defining young age-onset breast cancer","volume":"119","author":"Han","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_4","unstructured":"(2021, December 10). Cancer Research UK Breast Cancer Incidence (Invasive) Statistics by Age. Available online: https:\/\/www.cancerresearchuk.org\/health-professional\/cancer-statistics\/statistics-by-cancer-type\/breast-cancer\/incidence-invasive#ref-1."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.breast.2011.02.011","article-title":"Clinicopathologic characteristics and prognosis of young patients with breast cancer","volume":"20","author":"Han","year":"2011","journal-title":"Breast"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.1200\/JCO.2007.14.2471","article-title":"Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression","volume":"26","author":"Anders","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fredholm, H., Eaker, S., Frisell, J., Holmberg, L., Fredriksson, I., and Lindman, H. (2009). Breast Cancer in Young Women: Poor Survival Despite Intensive Treatment. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007695"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.jamcollsurg.2008.12.001","article-title":"Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease","volume":"208","author":"Gnerlich","year":"2009","journal-title":"J. Am. Coll. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e1027","DOI":"10.1016\/S2214-109X(20)30215-1","article-title":"Global burden and trends in premenopausal and postmenopausal breast cancer: A population-based study","volume":"8","author":"Heer","year":"2020","journal-title":"Lancet Glob. Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"77","DOI":"10.6004\/jnccn.2021.0001","article-title":"Genetic\/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology","volume":"19","author":"Daly","year":"2021","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15004","DOI":"10.1038\/nrdp.2015.4","article-title":"Menopause","volume":"1","author":"Davis","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1093\/ije\/dyu094","article-title":"Socioeconomic position, lifestyle factors and age at natural menopause: A systematic review and meta-analyses of studies across six continents","volume":"43","author":"Schoenaker","year":"2014","journal-title":"Int. J. Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1136\/jmedgenet-2015-103672","article-title":"Prevalence of BRCA1\/2 germline mutations in 21 401 families with breast and ovarian cancer","volume":"53","author":"Kast","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"380","DOI":"10.6004\/jnccn.2020.0017","article-title":"Genetic\/familial high-risk assessment: Breast, ovarian, and pancreatic, version 1.2020 featured updates to the NCCN guidelines","volume":"18","author":"Daly","year":"2020","journal-title":"JNCCN J. Natl. Compr. Cancer Netw."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S1470-2045(17)30891-4","article-title":"Germline BRCA mutation and outcome in young-onset breast cancer (POSH): A prospective cohort study","volume":"19","author":"Copson","year":"2018","journal-title":"Lancet. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s10549-017-4291-8","article-title":"Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer","volume":"164","author":"Rummel","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/s41436-018-0361-5","article-title":"Clinical Validity Assessment of Genes Frequently Tested on Hereditary Breast and Ovarian Cancer Susceptibility Sequencing Panels","volume":"21","author":"Lee","year":"2019","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1056\/NEJMoa1913948","article-title":"Breast Cancer Risk Genes\u2014Association Analysis in More than 113,000 Women","volume":"384","author":"Dorling","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/s41591-018-0009-7","article-title":"Carboplatin in BRCA1\/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial","volume":"24","author":"Tutt","year":"2018","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1038\/s41467-020-16142-7","article-title":"Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer","volume":"11","author":"Chopra","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.ygyno.2019.03.250","article-title":"The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up","volume":"153","author":"Harper","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/jnci\/djy147","article-title":"Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative","volume":"111","author":"Zimmer","year":"2019","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1007\/s10897-017-0069-8","article-title":"\u201cIt was an Emotional Baby\u201d: Previvors\u2019 Family Planning Decision-Making Styles about Hereditary Breast and Ovarian Cancer Risk","volume":"26","author":"Dean","year":"2017","journal-title":"J. Genet. Couns."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"234","DOI":"10.4274\/ejbh.galenos.2021.2021-4-3","article-title":"American Joint Committee on Cancer\u2019s Staging System for Breast Cancer, Eighth Edition: Summary for Clinicians","volume":"17","author":"Zhu","year":"2021","journal-title":"Eur. J. Breast Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_26","unstructured":"(2022, April 07). National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 3.2022. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/nscl.pdf."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nature12981","article-title":"Realizing the promise of cancer predisposition genes","volume":"505","author":"Rahman","year":"2014","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/bjc.2016.223","article-title":"An investigation of the association of genetic susceptibility risk with somatic mutation burden in breast cancer","volume":"115","author":"Zhu","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1073\/pnas.68.4.820","article-title":"Mutation and Cancer: Statistical Study of Retinoblastoma","volume":"68","author":"Knudson","year":"1971","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41586-019-1382-1","article-title":"Tumour lineage shapes BRCA-mediated phenotypes","volume":"571","author":"Jonsson","year":"2019","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13058-015-0618-8","article-title":"The molecular landscape of premenopausal breast cancer","volume":"17","author":"Liao","year":"2015","journal-title":"Breast Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumors","volume":"490","author":"Koboldt","year":"2012","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Olivier, M., Bouaoun, L., Villar, S., Robitaille, A., Cahais, V., Heguy, A., Byrnes, G., Le Calvez-Kelm, F., Torres-Mej\u00eda, G., and Alvarado-Cabrero, I. (2019). Molecular features of premenopausal breast cancers in Latin American women: Pilot results from the PRECAMA study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210372"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s10549-012-2375-z","article-title":"Prevalence of germline TP53 mutations in HER2-positive Breast Cancer Patients","volume":"139","author":"Rath","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67686","DOI":"10.18632\/oncotarget.11891","article-title":"Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline\/taxane-based chemotherapy","volume":"7","author":"Denkert","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Rom\u00e1n-Rosales, A.A., Garc\u00eda-Villa, E., Herrera, L.A., Gariglio, P., and D\u00edaz-Ch\u00e1vez, J. (2018). Mutant p53 gain of function induces HER2 over-expression in cancer cells. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4613-1"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9219","DOI":"10.1007\/s13277-014-2176-6","article-title":"Germline mutations of TP53 gene in breast cancer","volume":"35","author":"Damineni","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/s41416-021-01601-9","article-title":"Sensitive and robust liquid biopsy-based detection of PIK3CA mutations in hormone-receptor-positive metastatic breast cancer patients","volume":"126","author":"Suppan","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(21)00034-6","article-title":"Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4\/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study","volume":"22","author":"Rugo","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1590\/1806-9282.61.05.474","article-title":"Somatic mutations in breast and serous ovarian cancer young patients: A systematic review and meta-analysis","volume":"61","author":"Encinas","year":"2015","journal-title":"Rev. Assoc. Med. Bras."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41523-017-0051-5","article-title":"Functional germline variants as potential co-oncogenes","volume":"3","author":"Agarwal","year":"2017","journal-title":"NPJ Breast Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1056\/NEJM199601183340301","article-title":"BRCA1 Mutations in a Population-Based Sample of Young Women with Breast Cancer","volume":"334","author":"Langston","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1177\/000313481808401009","article-title":"Menopausal Status and Outcomes of BRCA Mutation Carriers with Breast Cancer","volume":"84","author":"Carlson","year":"2018","journal-title":"Am Surg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1055\/s-0036-1579759","article-title":"Li-Fraumeni Syndrome","volume":"5","author":"Correa","year":"2016","journal-title":"J. Pediatr. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/humu.23154","article-title":"Assessment of TP53 Polymorphisms and MDM2 SNP309 in Premenopausal Breast Cancer Risk","volume":"38","author":"Samuel","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1200\/JCO.2006.06.3024","article-title":"Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation","volume":"25","author":"Schmidt","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.cancergen.2015.02.006","article-title":"CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases","volume":"208","author":"Apostolou","year":"2015","journal-title":"Cancer Genet."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Apostolou, P., Dellatola, V., Papadimitriou, C., Kalfakakou, D., Fountzilas, E., Faliakou, E., Fountzilas, G., Romanidou, O., Konstantopoulou, I., and Fostira, F. (2021). CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects. Cancers, 13.","DOI":"10.3390\/cancers13092106"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1056\/NEJMoa2005936","article-title":"A Population-Based Study of Genes Previously Implicated in Breast Cancer","volume":"384","author":"Hu","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/gim.2016.147","article-title":"Genetic modifiers of CHEK2\u22171100delC-associated breast cancer risk","volume":"19","author":"Muranen","year":"2017","journal-title":"Genet. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1053\/j.gastro.2009.08.052","article-title":"Expanded extracolonic tumor spectrum in MUTYH-associated polyposis","volume":"137","author":"Vogt","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s10549-010-0801-7","article-title":"Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer","volume":"124","author":"Wasielewski","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s10549-012-1965-0","article-title":"MUTYH gene variants and breast cancer in a Dutch case-control study","volume":"134","author":"Out","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1309\/LMWZH57BRWOPR5RQ","article-title":"Computational Approach to Annotating Variants of Unknown Significance in Clinical Next Generation Sequencing","volume":"46","author":"Schulz","year":"2015","journal-title":"Lab. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"viii69","DOI":"10.1093\/annonc\/mdt312","article-title":"Variants of unknown significance in BRCA testing: Impact on risk perception, worry, prevention and counseling","volume":"24","author":"Richter","year":"2013","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1362\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:59:15Z","timestamp":1760140755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,29]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["genes13081362"],"URL":"https:\/\/doi.org\/10.3390\/genes13081362","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,29]]}}}